Overall Project Summary/Abstract Cancer is an evolutionary and ecological phenomenon driven by the fundamental forces of evolution: mutations, natural selection and genetic drift. It provides a classic example of multi-level selection. At the level of individual cancer cells, selection favors neoplastic proliferation; at the level of the host organism, selection favors cancer suppression. A full understanding of cancer hinges on an appreciation of this fundamental tension. Regulatory mechanisms at the organismal level determine evolutionary parameters at the cell level such as the somatic mutation rate and response to DNA damage. Cancer circumvents those constraints and changes the parameters of cell-level evolution, leading to malignancy and eventual host death. Thus, organismal and cell-level evolution feedback upon each other. To paraphrase Dobzhansky, nothing in cancer biology makes sense except in the light of evolution. This opens an opportunity. We may apply evolutionary and ecological theory to neoplastic progression and response to therapy. The mission of the Arizona Cancer and Evolution Center (ACE) is to advance our fundamental understanding of cancer and its clinical management through the development and application of evolutionary and ecological models to cancer biology. This mission spans scales from the evolution of cancer suppression mechanisms and cancer susceptibility across species (Project 1) down to the evolution of normal somatic cells (Project 2) and populations of cancer cells (Project 3). Project 1 will develop models of organismal evolution to predict cancer rates and cancer defenses across species. We will test those predictions using veterinary databases of cancer incidence in over 1,900 animal species, and examine the genomes of 57 mammalian species for evidence of adaptations to the selective pressure of cancer. In addition, Project 2 will test Project 1's model predictions of cancer defenses in primary cells from those same 57 mammalian species. Project 2 will also measure the fundamental forces of evolution in normal colonic and small intestine tissue from humans, mice and elephants to address a basic but poorly understood property of cancer: tissue-level differences in cancer susceptibility. Project 3 will develop novel evolutionary and ecological indices, based on models of cell-level evolution in neoplasms from Project 1, to predict long term therapeutic response and patient survival in stage 2&3, chemo- nave colorectal cancers. These indices will provide, for the first time, a classification system that the community can use to draw distinctions between tumors with different evolutionary dynamics, and thereby provide a foundation for the clinical management of this evolving disease. ACE will support the Cancer Systems Biology Consortium and the growing field of evolution and cancer by providing data, analytical tools, models, workshops, and tutorials to facilitate the use of those resources.